Abstract PROJECT 1: Identifying Asthma-causing RSV Strains and Elucidating the Mechanisms of RSV- mediated Asthma Development Respiratory syncytial virus (RSV) lower respiratory tract infection during infancy represents a common risk factor that is strongly and consistently associated with asthma. It also represents an asthma risk factor with the strongest body of evidence establishing a causal relationship. In the first funding cycle we have been the first group to ever sequence and identify RSV strains associated with significantly increased risk of recurrent wheezing outcomes, as well as differential immune response and airway microbial patterns. This proposal addresses the next logical series of questions: (1) are these RSV strains associated with later childhood asthma development, and (2) can we better understand the mechanisms of RSV-mediated asthma development by assessing the host response to these strains in vivo and in vitro? To test our hypotheses that there are RSV strains associated with enhanced risk of asthma development, and they act through eliciting differential acute response to infant infection, altering airway and immune development, and early life microbial patterns, we propose to extend longitudinal follow-up of the 1900 children enrolled in the established INSPIRE birth cohort who will be four at the end of the first U19 funding period. This will enable us to confirm if the RSV strains that we have identified to cause more severe infant morbidity and early wheezing outcomes are also associated with asthma, and the pathways through which these RSV strains cause asthma. We propose the following: (1) Identify RSV strains associated with asthma inception at ages 6 to 8 years; (2) Determine how RSV strains impact the host microbial environment during primary RSV infection; (3) Assess primary airway epithelial cell (AEC) response to asthma-causing RSV strains; (4) Determine RSV induced immune responses associated with asthma inception in the INSPIRE cohort. Ultimately this information may inform the design and development of a vaccine that prevents ?asthmagenic? RSV strains from predisposing to asthma development. The leadership team has worked in this area for 15 years, have an in-place infrastructure, established collaborations and ongoing cohort with detailed phenotyping and rich biospecimen repository making us well positioned to successfully carry out this novel and impactful study.